<p>Pyrimidines and their hybrid structures have remained an emerging research domain for organic chemists owing to their diversity in both synthetic and natural molecules and their distinct applications. Hence, developing strategies to improve the synthetic efficiencies of N-heterocycles and their timely assessment on biological targets is crucial. The incorporation of indole moieties into barbiturate structure represents a significant advancement in medicinal chemistry, offering enhanced therapeutic characteristics. Herein, we report a conventional and microwave-assisted, three-component domino reaction involving indole-3-carbaldehyde, heterocyclic primary amines, and barbituric acid or thiobarbituric acid in the presence of ceric ammonium nitrate to effectively synthesize a library of novel&#xa0;fused heterocyclic&#xa0;derivatives, which differ in terms of a pyridine, pyrimidine, pyrazine, thiazole, triazole, and tetrazole ring. FTIR, ¹H NMR, ¹³C NMR, and HRMS techniques were employed to validate the structural integrity. The mechanistic route involves the establishment of new C–C and C–N bonds by Knoevenagel condensation, Michael addition, and intramolecular ring closure. All derived molecules were evaluated for antimicrobial activity and bioactivity score. The existing methodology has been shown to be more operational, environmentally benign, with reduce time from hours to minutes, no use of harmful solvents, and column chromatography, resulting in higher purity and excellent yields (75–92%).</p> Graphic Abstract <p></p> <p>Multicomponent synthesis of pyrimidine fused derivatives using Intramolecular heterocyclization with indole-3-carbaldehyde, barbituric acid or thiobarbituric acid and various heterocyclic amines under microwave and reflux conditions</p>